In general, a bioreactor is a vessel in which a chemical reaction or process is carried out that involves an organism or biochemically active substance derived from an organism. In other words, bioreactors differ from conventional chemical reactors in that they support and control biological entities. Therefore, bioreactors must be designed to provide a higher degree of control over upsets and contaminations than conventional chemical reactors, they must provide a higher degree of selectivity, they must accommodate a wider range of reaction rates, etc. Furthermore, the evaluation of the integrity of the cell population contained within the bioreactor throughout the course of the bioreactor's use is required. While this often done by analyzing samples of the bioreactor's flow, there are benefits to being able to analyze the cell population of the bioreactor over time. The reaction parameters that must be controlled and optimized include substrate selection, amount, and configuration; cellular selection, patterning, culturing, and protection; water availability; oxygen availability; nutrient availability; temperature; pH; gas evolution; product and byproduct removal; flow rate, etc. Advantageously, bioreactors are used in the following exemplary applications, among others: bioartificial organs, organ and tissue simulation, drug discovery and testing, cell/tissue manufacturing, antibody production, and, in general, the study and use of biochemical reactions (including those involving organisms, substances derived from or affecting organisms, cellular structures, etc.). It will be readily apparent to those of ordinary skill in the art that there are other applications not specifically included in this list, both existing and future.
Tissue loss and organ failure are unfortunately suffered by patients on a daily basis. Yet for acute clinical cases, transplantation is the only end stage treatment currently available. In reality, the supply of donated tissues and organs is very limited, and interim options are needed. The use of bioreactors that provide an environment for maintaining cells while enabling them to perform key functions offers hope as an interim treatment. In such applications, these bioreactors are essentially bridges to transplantation. In the future, they may serve as substitutes for transplantation as well.
In the case of bio-artificial liver (BAL) devices, for example, a bioreactor is used to support viable hepatocytes, such that these hepatocytes may express high levels of differentiated function. BAL devices are typically classified as one of several types: capillary hollow fiber devices, suspension and encapsulation chambers, and perfused beds and scaffolds. Capillary hollow fiber devices have been rapidly developed for clinical trials. Unfortunately, these devices have the inherent physical limitations of constrained total mass diffusion distances, reduced capacities for cellular mass maintenance, and non-uniform cellular distributions. Suspension and encapsulation chambers provide a uniform microenvironment and the potential for scale up, but they offer poor cellular stability (e.g. suspension chambers) and barriers to nutrient transport (e.g. encapsulation chambers). In both cases, cells are exposed to unacceptably high shear forces. Perfused beds and scaffolds solve some of these problems, but, unfortunately, experience non-uniform perfusion, the clogging of membrane pores, and may also expose cells to unacceptably high shear forces. All of these devices make it difficult, if not impossible, to remove a fraction of the cellular space in process, without otherwise disrupting the reactions taking place.
Thus, what is still needed in the field is a bioreactor design that solves some or all of these problems.
In general, tissue function is modulated by the communication of cells with extracellular matrices, soluble factors, and other cells. The technologies used to explore the latter interaction (e.g., cell-to-cell)—such as micro-fabrication, micro-patterning, and the like—have typically been applied to flat plate in vitro cultures. Because flat plate in vitro cultures offer low surface area-to-volume ratios, it is difficult to scale them up to the cellular masses associated with bioreactors. Micro-fabrication and micro-patterning techniques, such a photolithography, photo-patterning, micro-contact printing, inkjet printing, laser guided direct writing, and cell spraying have been used to develop heterogeneous two-dimensional and three-dimensional co-cultures. Although co-culturing hepatocytes, the liver parenchymal cell, with support cells positively impacts hepatocyte function, for example, micro-fabrication and micro-patterning techniques may not readily be implemented in any of the BAL devices described above.
Thus, what is still needed in the field is a bioreactor design that provides an adaptable cellular space, among other things.